process for the separation of enantiomerically pure compounds

Abstract

The present patent application relates to an improved process for the separation of enantiomerically pure compounds. Specifically it relates to separation of enantiomerically enriched Rivastigmine, Duloxetine, Escitalopram and their intermediates in high yields.

1 . A process for separation of a required isomer from a first mixture of isomers, that includes:
 a) reacting the first mixture of isomers with a first optically pure acid or base to recover a first diastereomeric salt of unwanted isomer as solid;   b) reacting a second mixture of isomers obtained from the mother liquors in step a) with a second optically pure acid or base having opposite rotation with respect to the first optically pure add or base to form a second diastereomeric salt of required isomer as solid; and   c) converting the second diastereomeric salt to the required isomer.   
     
     
         2 . The process of  claim 1 , wherein the first mixture of isomers comprises of about 50% or more of the unwanted isomer. 
     
     
         3 . The process of  claim 1 , wherein the first mixture of isomers comprises about 60% or more of the unwanted isomer. 
     
     
         4 . The process of  claim 1 , wherein the second mixture of isomers comprises about 60% or more of the required isomer. 
     
     
         5 . The process of  claim 1 , wherein the first mixture of isomers is obtained by an asymmetric synthesis or a stereo selective synthesis. 
     
     
         6 . The process of  claim 1 , wherein the first mixture of isomers is obtained by processing the mother liquors obtained during the resolution of a racemic mixture using an optically pure acid or base. 
     
     
         7 . The process of  claim 1 , wherein said optically pure acid comprises mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, and camphor sulfonic acid. 
     
     
         8 . The process of  claim 1 , wherein said optically pure base comprises 1-phenylethylamine, ephedrine, 2-amino-1-butanol, 2-amino-1-phenyl-1,3-propanediol, 1-naphthyl-1-ethylamine, (−)-quinine, (+)-quinidine, (−)-brucine and (+)-dehydroabietylamine N-octyl-D-glucomine. 
     
     
         9 . The process of  claim 1 , wherein the reaction is carried out in a solvent comprises of methanol, ethanol or isopropanol; acetone, methyl ethyl ketone or methyl isoburyl ketone. 
     
     
         10 . The process of  claim 1 , wherein the reaction temperature range is from about 20° C. to 80° C. 
     
     
         11 . The process of  claim 1 , wherein the reaction of step c) comprises treating the second diasteromeric salt with a base or an acid. 
     
     
         12 . The process of  claim 11 , wherein the base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia; and mixtures thereof. 
     
     
         13 . The process of  claim 11 , wherein the acid comprises hydrochloric acid, sulfuric acid, and acetic acid. 
     
     
         14 . A process for separation of Rivastigmine from a first mixture of isomers which process includes:
 a) reacting the first mixture of isomers with (−) DPTTA to recover (R)-Rivastigmine (−) DPTTA salt as solid;   b) reacting a second mixture of isomers obtained from the mother liquors in step a) with (+) DPTTA to form Rivastigmine (+) DPTTA salt as solid; and   c) converting the Rivastigmine (+) DPTTA salt to Rivastigmine.   
     
     
         15 . The process of  claim 14 , wherein the reaction is carried out in a solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, and ethyl acetate. 
     
     
         16 . The process of  claim 14 , wherein the reaction of step c) comprises treating the Rivastigmine (+) DPTTA salt with a base. 
     
     
         17 . The process of  claim 16 , wherein said base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia; and mixtures thereof. 
     
     
         18 . The process of  claim 14  which further comprises converting Rivastigmine to a pharmaceutically acceptable salt. 
     
     
         19 . A process for separation of S-(−)-1-(3-methoxyphenyl)ethanamine from a first mixture of isomers, which process includes:
 a) reacting the first mixture of isomers with D-(−) Mandelic acid (MA) to recover R-(+)-1-(3-methoxyphenyl)ethanamine D-(−) MA salt as solid; 
 b) reacting a second mixture of isomers obtained from the mother liquors in step a) with L (+) MA to form S-(−)-1-(3-methoxyphenyl)ethanamine L (+) MA as solid; and 
 c) converting the S-(−)-1-(3-methoxyphenyl)ethanamine L (+) MA salt to S-(−)-1-(3-methoxyphenyl)ethanamine. 
 
     
     
         20 . A process for separation of S-(−)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine from a first mixture of isomers, which process includes:
 a) reacting the first mixture of isomers with D-(−) MA to recover R-(+)-N,N-dimethyl-3-hydroxy-3-(2-thienyl propanamine D-(−) MA salt as solid; 
 b) reacting a second mixture of isomers obtained from the mother liquors of step a) with L (+) MA to form S-(−)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine L (+) MA salt as solid; and 
 c) converting the S-(−)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine L (+) MA salt to S-(−)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine. 
 
     
     
         21 . A process for separation of (−)4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile (escitalopram diol) from a first mixture of isomers, which process includes
 a) reacting the first mixture of isomers with (−) DPTTA to obtain (+)4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile (−) DPTTA salt as solid; 
 b) reacting a second mixture of isomers obtained from the mother liquors of step a) with (+) DPTTA to form escitalopram diol (+) DPTTA salt as solid; and 
 c) converting the escitalopram diol (+) DPTTA salt to Escitalopram or a salt thereof. 
 
     
     
         22 . (canceled) 
     
     
         23 . A method of using the enantiomerically pure intermediates obtained according to the process of present application in the preparation of active pharmaceutical ingredients including Rivastigmine, Duloxetine, Escitalopram or a salt thereof. 
     
     
         24 . The process of  claim 18  wherein said salt is hydrogentartrate salt.